A comprehensive overview of the complex world of the endo- and sarcoplasmic reticulum Ca2+-leak channels.

Inside cells, the endoplasmic reticulum (ER) forms the largest Ca2+ store. Ca2+ is actively pumped by the SERCA pumps in the ER, where intraluminal Ca2+-binding proteins enable the accumulation of large amount of Ca2+. IP3 receptors and the ryanodine receptors mediate the release of Ca2+ in a controlled way, thereby evoking complex spatio-temporal signals in the cell. The steady state Ca2+ concentration in the ER of about 500 μM results from the balance between SERCA-mediated Ca2+ uptake and the passive leakage of Ca2+. The passive Ca2+ leak from the ER is often ignored, but can play an important physiological role, depending on the cellular context. Moreover, excessive Ca2+ leakage significantly lowers the amount of Ca2+ stored in the ER compared to normal conditions, thereby limiting the possibility to evoke Ca2+ signals and/or causing ER stress, leading to pathological consequences. The so-called Ca2+-leak channels responsible for Ca2+ leakage from the ER are however still not well understood, despite over 20 different proteins have been proposed to contribute to it. This review has the aim to critically evaluate the available evidence about the various channels potentially involved and to draw conclusions about their relative importance.